Overview: Enzyme-catalyzed Enantioselective Biotransformation of Chiral Active Compounds Used in Hypertension Treatment

2020 ◽  
Vol 24 (23) ◽  
pp. 2782-2791
Author(s):  
Joanna Chałupka ◽  
Adam Sikora ◽  
Aleksandra Kozicka ◽  
Michał Piotr Marszałł
Keyword(s):  
Kinetic Resolution ◽  
Enzymatic Reactions ◽  
Reaction Conditions ◽  
Enantiomerically Pure ◽  
Pharmaceutical Ingredients ◽  
Enzymatic Kinetic Resolution ◽  
Treatment Of Hypertension ◽  
Pure Compounds ◽  
Β Blockers ◽  
Asymmetric Carbon

Enzymatic kinetic resolution is one of the methods which allows for the synthesis of enantiomerically pure various active pharmaceutical ingredients. In contrast to chemical routes, enzymatic reactions have characteristics, including mild reaction conditions, a few byproducts, and relatively high activity of the used enzymes. β-adrenolytic drugs are widely used in the treatment of hypertension and cardiovascular disorders. Due to the fact that β- blockers possess an asymmetric carbon atom in their structure, they are presented in two enantiomeric forms. It was reported by many studies that only the (S)-enantiomers of these drugs possess the desired therapeutic effect, whereas the administration of the racemate may cause dangerous side effects, such as bronchoconstriction or diabetes. Nevertheless, β- blockers are still commercially available drugs mainly used in medicine as racemates, whereas there are several methods that are widely used in order to obtain enantiomerically pure compounds.

scholarly journals Current applications of kinetic resolution in the asymmetric synthesis of substituted pyrrolidines

2021 ◽  
Author(s):  
Sian Stephanie Berry ◽  
Simon Jones
Keyword(s):  
Asymmetric Synthesis ◽  
Traditional Method ◽  
Kinetic Resolution ◽  
Biologically Active ◽  
Enantiomerically Pure ◽  
Pure Compounds

Chiral substituted pyrrolidines are key elements in various biologically active molecules and are therefore valuable synthetic targets. One traditional method to enantiomerically pure compounds is the application of kinetic resolution....

scholarly journals The production of enantiomerically pure 1-phenylethanol by enzymatic kinetic resolution method using response surface methodology

2020 ◽  
Vol 44 (5) ◽  
pp. 1352-1365
Author(s):  
Ayşe BOZAN ◽  
Rahime SONGÜR ◽  
Ülkü MEHMETOĞLU
Keyword(s):  
Response Surface Methodology ◽  
Reaction Time ◽  
Response Surface ◽  
High Performance ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Reaction Parameters ◽  
Enantiomerically Pure ◽  
Enzymatic Kinetic Resolution ◽  
Optimum Reaction

As the enantiomers of 1-phenylethanol are valuable intermediates in several industries, the lipase catalyzed kinetic resolution of (R,S) -1-phenylethanol is a relevant research topic. In this study, the goal was to determine the optimum reaction parameters to produce enantiomerically pure 1-phenylethanol by lipase (Novozyme 435) catalyzed kinetic resolution using response surface methodology (RSM). Reactions were performed with 40–400 mM (R,S)-1-phenylethanol, 120–1200 mM vinyl acetate and 2–22 mg/ mL biocatalyst concentrations (BCL), at 20–60 °C and with a stirring rate of 50–400 rpm for 5–120 min. The samples were analyzed using high performance liquid chromatography (HPLC) with a Chiralcel OB column. Optimum reaction parameters to reach 100% enantiomeric excess for the substrate (ees) were determined as follows: substrate concentration (Cs): 240 mM, BCL: 11 mg/mL, at 42 °C with a reaction time of 75 min. Model validation was performed using these conditions and ees was calculated as 100%, which indicates the predicted model was efficient and accurate. When compared to the literature, it was observed that the reaction time decreased significantly. This is an important result considering the industrial scale perspective.

scholarly journals Biocatalysis in continuous-flow mode: A case-study in the enzymatic kinetic resolution of secondary alcohols via acylation and deacylation reactions mediated by Novozym 435®

Biocatalysis ◽  
2017 ◽  
Vol 3 (1) ◽  
Author(s):  
Juliana Christina Thomas ◽  
Martha Daniela Burich ◽  
Pamela Taisline Bandeira ◽  
Alfredo Ricardo Marques de Oliveira ◽  
Leandro Piovan
Keyword(s):  
Continuous Flow ◽  
Energy Use ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Flow Mode ◽  
Enzymatic Reactions ◽  
Secondary Alcohols ◽  
Batch Mode ◽  
Enzymatic Kinetic Resolution

AbstractEnzymatic kinetic resolution reactions are a well-established way to achieve optically active compounds. When enzymatic reactions are combined to continuous-flow methodologies, other benefits are added, including reproducibility, optimized energy use, minimized waste generation, among others. In this context, we herein report a case study involving lipase-mediated transesterification by acylation and deacylation reactions of secondary alcohols/esters in batch and continuous-flow modes. Acylation reactions were performed with high values of enantiomeric excess (72 up to >99%) and enantioselectivity (E > 200) for both batch and continuous-flow modes. On the other hand, for deacylation reactions using n-butanol as nucleophile, enatiomeric excess ranged between 38 to >99% and E from 6 to >200 were observed for batch mode. For deacylation reactions in continuous-flow mode, results were disappointing, as in some cases, very low or no conversion was observed. Enantiomeric excess ranged from 16 to >99% and enantioselectivity from 5 to >200 were observed. In terms of productivity, continuous-flow mode reactions were superior in both strategies (acylation: r from 1.1 up to 18.1-fold higher, deacylation: 2.8 up to 7.4- fold higher in continuous-flow than in batch mode).

scholarly journals Altering the Stereoselectivity of Whole-Cell Biotransformations via the Physicochemical Parameters Impacting the Processes

Catalysts ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 781
Author(s):  
Agnieszka Raczyńska ◽  
Joanna Jadczyk ◽  
Małgorzata Brzezińska-Rodak
Keyword(s):  
Culture Conditions ◽  
Biologically Active ◽  
Enantiomerically Pure ◽  
Whole Cells ◽  
Chiral Compounds ◽  
Physicochemical Factors ◽  
Pure Compounds ◽  
Genetic Level ◽  
Prochiral Ketones ◽  
Optically Pure

The enantioselective synthesis of organic compounds is one of the great challenges in organic synthetic chemistry due to its importance for the acquisition of biologically active derivatives, e.g., pharmaceuticals, agrochemicals, and others. This is why biological systems are increasingly applied as tools for chiral compounds synthesis or modification. The use of whole cells of “wild-type” microorganisms is one possible approach, especially as some methods allow improving the conversion degrees and controlling the stereoselectivity of the reaction without the need to introduce changes at the genetic level. Simple manipulation of the culture conditions, the form of a biocatalyst, or the appropriate composition of the biotransformation medium makes it possible to obtain optically pure products in a cheap, safe, and environmentally friendly manner. This review contains selected examples of the influence of physicochemical factors on the stereochemistry of the biocatalytic preparation of enantiomerically pure compounds, which is undertaken through kinetically controlled separation of their racemic mixtures or reduction of prochiral ketones and has an effect on the final enantiomeric purity and enantioselectivity of the reaction.

scholarly journals Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol

Catalysts ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 503
Author(s):  
Morten Gundersen ◽  
Guro Austli ◽  
Sigrid Løvland ◽  
Mari Hansen ◽  
Mari Rødseth ◽  
...  
Keyword(s):  
Building Block ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Catalytic Amount ◽  
Building Blocks ◽  
Β Blocker ◽  
Β Blockers ◽  
Optical Rotations ◽  
Reported Data ◽  
By Products

Sustainable methods for producing enantiopure drugs have been developed. Chlorohydrins as building blocks for several β-blockers have been synthesized in high enantiomeric purity by chemo-enzymatic methods. The yield of the chlorohydrins increased by the use of catalytic amount of base. The reason for this was found to be the reduced formation of the dimeric by-products compared to the use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previously reported data of similar compounds. The enantiomers of the chlorohydrin building blocks were obtained by kinetic resolution of the racemate in transesterification reactions catalyzed by Candida antarctica Lipase B (CALB). Optical rotations confirmed the absolute configuration of the enantiopure drugs. The β-blocker (S)-practolol ((S)-N-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) was synthesized with 96% enantiomeric excess (ee) from the chlorohydrin (R)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide, which was produced in 97% ee and with 27% yield. Racemic building block 1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol for the β-blocker pindolol was produced in 53% yield and (R)-1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol was produced in 92% ee. The chlorohydrin 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, a building block for a derivative of carteolol was produced in 77% yield. (R)-7-(3-Chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one was obtained in 96% ee. The S-enantiomer of this carteolol derivative was produced in 97% ee in 87% yield. Racemic building block 5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, building block for the drug carteolol, was also produced in 53% yield, with 96% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. (S)-Carteolol was produced in 96% ee with low yield, which easily can be improved.

Stereochemistry of epoxide carbonylation using bimetallic Lewis acid/metal carbonyl complexes

2004 ◽  
Vol 76 (3) ◽  
pp. 557-564 ◽  
Author(s):  
Y. D. Y. L. Getzler ◽  
Viswanath Mahadevan ◽  
E. B. Lobkovsky ◽  
G. W. Coates
Keyword(s):  
Lewis Acid ◽  
Kinetic Resolution ◽  
Metal Carbonyl ◽  
Carbonyl Complexes ◽  
Enantiomerically Pure ◽  
Metal Carbonyl Complexes ◽  
Pure Complex

The stereochemistry of epoxide carbonylation using bimetallic [Lewis acid]+[Co(CO)4]- complexes is reported. The achiral complex [(salph)Al(THF)2][Co(CO)4] stereospecifically carbonylates cis- and trans-2-butene oxide to the trans- and cis-β-lactones, respectively. Preliminary experiments regarding the carbonylative kinetic resolution of racemic trans-2-butene oxide using the enantiomerically pure complex [(R,R-salcy)Al(THF)2][Co(CO)4] are also reported.

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